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BACKGROUND: The diagnosis and prognosis of diffuse axonal injury (DAI) remain challenging. This research aimed to analyze the impact on activities of daily living (ADL), functional outcomes, quality of life (QoL), and the association between lesion severity and DAI location identified through imaging exams. METHODS: This prospective cohort study included 95 patients diagnosed with DAI. Data were collected at admission, three, six, and twelve months post-injury. The associations between variables were evaluated using a mixed-effects model. RESULTS: Functional recovery and QoL improved between three and twelve months after DAI. An interaction was observed between independence in performing ADL and subarachnoid hemorrhage (p = 0.043) and intraventricular hemorrhage (p = 0.012). Additionally, an interaction over time was observed between the Glasgow Outcome Scale (GOS) and DAI severity (p < 0.001), brain lesions (p = 0.014), and the Disability Rating Scale (DRS) with injury in brain hemispheres (p = 0.026) and Adams classification (p = 0.013). Interaction effects over time were observed with the general health perceptions and energy/vitality domains with intraventricular hemorrhage, and the social functioning domain with the obliteration of basal cisterns and Gentry's classification. CONCLUSION: The use of CT in the acute phase of DAI is important for predicting outcomes. The severity and location of DAI are associated with functional outcomes, ADL, and QoL.

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Resumen La proteína precursora del β- Amiloide (β-APP) es una glicoproteína de membrana y un componente habitual de las neuronas. Tiene funciones en el crecimiento y la adhesión celular tras un traumatismo. Es transportada mediante transporte rápido axonal anterógrado y se acumula dentro de las neuronas cuando se daña citoesqueleto. Este proceso es activo, es decir consume energía. El β-APP no es específico de los traumatismos. Se acumula en cualquier circunstancia en la que se dañen los axones, tal como la hipoxia, alteraciones metabólicas, y cualquier otra causa de edema cerebral y aumento de la presión intracraneal que puedan conducir a un daño axonal difuso (DAI) En el presente estudio estudiamos la expresión de esta proteína en casos de traumatismo cráneo-encefálico con diferente evolución cronológica El daño del citoesqueleto producido por la proteólisis, junto con la alteración de las quinasas y las fosfatasas, aumentan la permeabilidad de la membrana, lo que provoca la entrada de calcio en la célula que, a su vez, activa la calmodulina que hace que los neurofilamentos se compacten, los microtúbulos desaparezcan y se rompa la espectrina. Esta disrupción del citoesqueleto tiene como consecuencia que las sustancias que se transportan a su través, se acumulen, sobre todo en las zonas afectadas por el DAI. Al final de todo este proceso, los axones se rompen, lo que se conoce como axotomía secundaria. El estudio de la acumulación del β-APP es útil para valorar la extensión del DAI y para determinar el tiempo de supervivencia tras el traumatismo o cualquier otro daño cerebral.

Abstract β-Amyloid Precursor Protein (β-APP) is a membrane glycoprotein and a common component of neurons. It is involved in adhesion and cell growth processes after traumatic events. It is carried by anterograde fast axonal transport, and it accumulates inside neurons when the cytoskeleton is damaged. This is a vital biochemical process that consumes energy. β-APP is not specific of traumatic events. It accumulates in any case of axonal damage, whatever its cause may be, like hypoxia, metabolic disorders, and any other circumstances that lead to brain swelling and intracranial pressure rising and in consequence to Diffuse Axonal Injury (DAI). In this study we review the expression of this protein in cases of traumatic brain injury with different chronological evolution. The damage of cytoskeleton due to proteolysis in addition to the disturbance of kinases and phosphatases increase the permeability of the membrane. Calcium gets into the cell and activates calmodulin, thus neurofilaments compact, microtubules disappear and spectrin breaks. This disruption of the cytoskeleton has as consequence that the transported substances accumulate in the most affected areas by DAI. At the end of this process axon breaks, which is known as secondary axotomy. The study of the accumulation of β-APP is useful to assess the extent of DAI and to determine the time elapsed after trauma or another insult to CNS.

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BACKGROUND: Diffuse axonal injury (DAI) is a frequent mechanism of traumatic brain injury (TBI) that triggers a sequence of parenchymal changes that progresses from focal axonal shear injuries up to inflammatory response and delayed axonal disconnection. OBJECTIVE: The main purpose of this study is to evaluate changes in the axonal/myelinic content and the brain volume up to 12 months after TBI and to correlate these changes with neuropsychological results. METHODS: Patients with DAI (n = 25) were scanned at three time points after trauma (2, 6, and 12 months), and the total brain volume (TBV), gray matter volume, and white matter volume (WMV) were calculated in each time point. The magnetization transfer ratio (MTR) for the total brain (TB MTR), gray matter (GM MTR), and white matter (WM MTR) was also quantified. In addition, Hopkins verbal learning test (HVLT), Trail Making Test (TMT), and Rey-Osterrieth Complex Figure test were performed at 6 and 12 months after the trauma. RESULTS: There was a significant reduction in the mean TBV, WMV, TB MTR, GM MTR, and WM MTR between time points 1 and 3 (p < .05). There was also a significant difference in HVLT-immediate, TMT-A, and TMT-B scores between time points 2 and 3. The MTR decline correlated more with the cognitive dysfunction than the volume reduction. CONCLUSION: A progressive axonal/myelinic rarefaction and volume loss were characterized, especially in the white matter (WM) up to 1 year after the trauma. Despite that, specific neuropsychological tests revealed that patients' episodic verbal memory, attention, and executive function improved during the study. The current findings may be valuable in developing long-term TBI rehabilitation management programs.

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BACKGROUND: Neuropsychological rehabilitation is a crucial component of medical care for patients with diffuse axonal injury (DAI). However, current cognitive intervention programs directed to favor the training of specific domains individually have shown controversial results. Here, we evaluated the effectiveness of a neuropsychological rehabilitation program directed to favor training of attention, memory, visuospatial abilities, and executive functioning together in a patient with severe traumatic brain injury (TBI)-associated DAI. CASE PRESENTATION: A 26-year-old Hispanic woman with a recent history of a severe TBI attended our center complaining of memory problems, dysarthria, and difficulty in planning. A comprehensive cognitive assessment revealed dysfunction in sustained, selective, and divided attention, alterations in memory, planning, and organization of executive behavior, as well as impairment of visuospatial cognitive functions. The patient underwent a 24-week neuropsychological rehabilitation program directed to favor attention, memory, visuospatial abilities, and executive functioning together. After the cognitive intervention, we observed a better patient's performance in tasks requiring sustained, selective, and divided attention, improvement of encoding and retrieval memory problems, use of spatial relationships, planning, and organization of behavior skills. We also observed generalization effects on other domains, such as learning, mental flexibility, inhibition functions, and language. CONCLUSIONS: In conclusion, our results suggest that neuropsychological rehabilitation programs favoring multiple domains together are useful in reestablishing cognitive deficits in patients with severe DAI.

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Paroxysmal sympathetic hyperactivity may appear after brain injury. Its clinical manifestations are sporadic and self-limited crisis of arterial hypertension, hyperthermia, tachycardia, hyperhidrosis, muscle tension, sialorrhea and mydriasis. These subside with the administration of morphine and beta-blockers. It may be caused by a dysautonomia leading to increased levels of catecholamines due to the lack of brain regulation. We report a 19 years-old man with a history of illicit drug and alcohol consumption, with a secondary axonal injury due to a cranioencephalic trauma. During hospitalization, he had recurrent, self-limited episodes of dysautonomia. An infectious cause was discarded. When morphine was administrated suspecting the presence of pain, the crisis subsided, which helped to establish the diagnosis of paroxysmal sympathetic hyperactivity.

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PURPOSE: Diffuse axonal injury (DAI) is the rupture of multiple axons due to acceleration and deceleration forces during a closed head injury. Most traumatic brain injuries (TBI) have some degree of DAI, especially severe TBI. Computed tomography (CT) remains the first imaging test performed in the acute phase of TBI, but has low sensitivity for detecting DAI, since DAI is a cellular lesion. The aim of this study is to search in the literature for CT signs, in the first 24 h after TBI, that may help to differentiate patients in groups with a better versus worst prognosis. METHODS: We searched for primary scientific articles in the PubMed database, in English, indexed since January 1st, 2000. RESULTS: Five articles were selected for review. In the DAI group, traffic accidents accounted 70% of the cases, 79% were male, and the mean age was 41 years. There was an association between DAI and intraventricular hemorrhage (IVH) and traumatic subarachnoid hemorrhage (tSAH); an association between the IVH grade and number of corpus callosum lesions; and an association between blood in the interpeduncular cisterns (IPC) and brainstem lesions. CONCLUSION: In closed TBI with no tSAH, severe DAI is unlikely. Similarly, in the absence of IVH, any DAI is unlikely. If there is IVH, patients generally are clinically worse; and the more ventricles affected, the worse the prognosis.

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We report a case of traumatic brain injury treated with Cerebrolysin, a neurorecovery stimulating agent. Our therapeutic approach was based on the pathophysiology of traumatic brain injury and, in particular, of diffuse axonal injury. The patient registered marked improvement in mood and cognitive performance, indicating the effectiveness of multimodal and multidisciplinary interventions after traumatic brain injury.

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Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation of axonal pathology relies upon its detection. APP+ swellings first appear as varicosities along intact axons, which can ultimately undergo secondary disconnection to leave a terminal "axon bulb" at the disconnected, proximal end. However, sites of disconnection are difficult to determine with certainty using standard, thin tissue sections, thus limiting the comprehensive evaluation of axon degeneration. The tissue-clearing technique, CLARITY, permits three-dimensional visualization of axons that would otherwise be out of plane in standard tissue sections. Here, we examined the morphology and connection status of APP+ swellings using CLARITY at 6 h, 24 h, 1 week and 1 month following the controlled cortical impact (CCI) model of TBI in mice. Remarkably, many APP+ swellings that appeared as terminal bulbs when viewed in standard 8-µm-thick regions of tissue were instead revealed to be varicose swellings along intact axons when three dimensions were fully visible. Moreover, the percentage of these potentially viable axon swellings differed with survival from injury and may represent the delayed onset of distinct mechanisms of degeneration. Even at 1-month post-CCI, ~10% of apparently terminal bulbs were revealed as connected by CLARITY and are thus potentially salvageable. Intriguingly, the diameter of swellings decreased with survival, including varicosities along intact axons, and may reflect reversal of, or reduced, axonal transport interruption in the chronic setting. These data indicate that APP immunohistochemistry on standard thickness tissue sections overestimates axon disconnection, particularly acutely post-injury. Evaluating cleared tissue demonstrates a surprisingly delayed process of axon disconnection and thus longer window of therapeutic opportunity than previously appreciated. Intriguingly, a subset of axon swellings may also be capable of recovery.

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